Current treatment methods for cancer, including radiation therapy, surgery, and chemotherapy, are known to have limited effectiveness. For example, breast cancer annually kills tens of thousands of people in the United States; the numbers are surpassed only by the number of lung cancer deaths. A substantial increase in the number of new cases of prostate cancer has accompanied the aging of the American male population. One estimate suggests that between the years 1990 and 2000, cases of prostate cancer will increase by 90 percent and deaths from prostate cancer will increase by 37 percent (Carter and Coffey, 1990). Prostate cancer currently accounts for 12.3 percent of cancer deaths in men (Gittes, 1991).
Even with the implementation of educational programs designed to curb smoking and eating habits, cancer mortality rates will remain high well into the 21st century. The morbidity and mortality associated with cancer exacts an ever-increasing financial toll on an already overburdened health-care system. Clearly, effective agents that have cytotoxicity and specificity for cancer cells would fill a long and unmet need.
Although vaccines have been enormously successful in preventing many important viral diseases, there is still a pressing need for effective treatment of viral infections. Unfortunately, antiviral chemotherapy has lagged far behind antibiotic treatment for bacterial infections. Until recently, it was very difficult to find drugs that would inhibit viral functions without simultaneously damaging the closely related host cell mechanisms. With the recognizing of viral enzymes and proteins that can serve as molecular targets for drugs (Crumpacker, 1989), antiviral chemotherapy has become a practical reality. Unfortunately, the increasing clinical use of antiviral agents has begun to produce resistant viral strains (Hirsch and Schooley, 1989).
Depression is a serious public health problem with prevalence rates ranging from 5% to 21.3%. These illnesses are present in 3.6% to 7.9% of the population in a one-year period (Angst and Stabl, 1992). In the United States, these numbers translate into 8 million to 36 million adults at risk for depression in their lifetime. Depressed patients are about 20% more likely to attempt suicide and 15% of patients with major depression eventually die by suicide. Although a tremendous improvement in the treatment of these illnesses has been made, approximately 25% of depressed patients have a poor response to any particular antidepressant. Prior to treatment, it is not currently possible to predict which patient will respond. Also, the time for maximal therapeutic benefit to occur is at least one month or longer. Many currently available antidepressants have serious side effects. In view of the aforementioned factors, those of skill in this art have sought new antidepressants that elicit a faster response and have significantly reduced side effects.
The immune response is mediated by two different classes of lymphocytes: T cells, that develop in the thymus, are responsible for cell-mediated immunity; and B cells, that develop in bone marrow or fetal liver, produce antibodies. Thus, T cells are a major component of the immune system and, as such, they play a pivotal role in virtually all aspects of the immune system. The majority of T cells play a regulatory role in immunity, acting either to enhance (helper cells) or suppress (suppressor cells) the response of other white blood cells. T cells are involved in cell-mediated immunity, the production of cytokines, autoimmunity, tolerance, inflammation, and organ rejection. An imbalance of T cell function or their number results in serious disease states. For example, activated T helper cells and mononuclear cells as well as pro-inflammatory cytokines (Menter and Barker, 1991) are involved in psoriasis and arthritis and can be present as severe inflammatory dermatosis in patients with acquired immunodeficiency syndrome (Duvic, M., 1990). The immunodeficiency virus targets T helper cells and this infection causes a severe reduction in helper type T cells by killing them. The resulting imbalance in the number of helper T cells compromises the patient's overall immune system, rendering it ineffective even against common infections. On the other hand, hyperproliferation of T cells results in T cell leukemia. Further, T lymphocytes appear to play a central role in the pathogenesis of asthma (Kline and Hunninghake, 1994). Thus, there is an urgent need for drugs that cause a desirable modulation of T cells for the control of treatment of cancer, AIDS, arthritis, psoriasis and other diseases of the immune system.
The synthesis of barbituric acid starting from hydurilic and diliuric acid was first accomplished by Baeyer (1864). Barbital, a derivative of barbituric acid, was prepared by Conrad and Guthzeit (1882). The pharmacological properties of barbital were later described (Fisher and Mering, 1903; Baeyer, F. & Co., Ger. Pat. 247952, Mar. 04, 1911).
The barbiturates act as nonselective central nervous system depressants and are primarily used as sedative hypnotics and anti-convulsants in subhypnotic doses (Myer and Rollet, 1964). For example, the sodium salts of amobarbital, pentobarbital, phenobarbital, and secobarbital are presently available as prescription drugs. It is important to note that the basic structure common to these drugs, barbituric acid, in itself has no central nervous system activity. Central nervous system activity is obtained by substituting certain alkyl, alkenyl or aryl groups on the pyrimidine ring structure. The role of gamma-aminoisobutyric acid on anticonvulsant activity has been described (Hafeley, 1980).
Certain N-substituted barbituric acids with halogen atoms at C-5 display antiviral properties, including influenza virus (Ger. Offen 2003994, Belg. Pat. 622081). Other compounds such as 5-azidobarbituric acid and phenobarbital-papaverine act as an antispasmolytic (Toth et al., (Alkaloida Vegyeszeti Gyar), Hung, Teljes HU 19767 (Cl. C07D239/62), Apr. 28, 1981; Minelli, 1968; Canellas, Fr. M-3578 (Cl. A61K, C07d), Nov. 08, 1965; Saratikov et al., 1973; Spiridonova and Gol'tsev, 1976). N-arylbarbituric and N-arylthiobarbituric acids act as anti-inflammatory agents (Pol. Pat. 106804; Pol. Pat. 110668; Zawisza et al., 1981; Sladowska, 1977).
Antitumor activity has been reported for 5-formylimidoylbarbituric acid derivatives (Meyer and Althnus, 1979; Kreutzberger, 1978); similar effects have been reported for N-phenyl-thiobarbituric acid under in vivo conditions (Singh and Behl, 1980). For 5,5-disubstituted barbituric acids, activities such as analgesic (Ger. Offen 1 817958; Vida et al., 1975, 1974a, 1974b; Jap. Pat. 20595), antidiabetic (Deshpande and Datta, 1972), antiepileptic (Wirth, 1975), antiinflammatory (Pol. Pat. 76936, Jap. Pat. 6807948), antigenic (Kuroiwa et al., 1980), antithyroid (Astwood et al., 1945), antithrombin (Rehse and Kapp, 1982), cardiotonic (Belonozhko et al., 1966), stimulation of plant growth (USSR Pat. 497006), diuretic (Ger. Offen. 2216619), fungicide and insecticide (Ger. Offen. 2719733; Ger. Offen., 2719777; U.S. Pat. No. 3,919,232; Gorter, 1970), herbicide (Ger. Offen. 2524578), inhibition of gastric secretion (Dinno et al., 1972; Kakemi et al., 1967), hypoglycemic (Shoeb et al., 1967), muscular relaxing (U.S. Pat. No. 3,919,427; U.S. Pat. No. 3,148,189; Bobranski et al., 1961), and hypotensive effects (Toth and Makleit, 1981) have been reported.
Only a few derivatives of thiobarbituric acid were prepared until 1935, when it was discovered that these compounds possess anesthetic properties (Miller et al., 1935; Tabern and Volwiler, 1935; Miller et al., 1936). Derivatives with a thiosemicarbazide group at the C-5 position and phenylhydrazones of 5-monoalkylbarbituric acids display antimicrobial properties (Kamel, 1982; Chemishev, 1979; Chemishev, 1981). The presence of allyl or n-decyl groups also confers antimicrobial properties (Beres et al., 1980; Beres et al., 1974).
Many barbituric acid derivatives such as thiobarbituric acid and its derivatives have also been used in the synthesis of dyes and pigments or intermediates in the preparation of dyes (Gysling, 1949; Schmidt, 1959; Sabata and Rout, 1962). Certain barbituric acid derivatives are photooxidation products of Merocyanine 540, and are reportedly useful as anticancer and antiviral agents (U.S. Pat. No. 5,312,919).
Alloxan has been used as a pretreatment for inhibiting the "take" of transplanted tumor cells (Altman and Spoladore, 1970); and has been used for inducing diabetes (Cherry and Glucksmann, 1971).
The prior art lacks reference to the barbituric acid analogs provided by the present invention as having anti-cancer, anti-pathogenic, immune-stimulating or anti-depressant properties. Because the diseases and other medical conditions that the present invention addresses are severe health problems and because known treatment procedures are not completely satisfactory, persons skilled in the art have searched for improvements.